The efficiency of many experimentally based developments can be increased by miniaturization, automation and parallel operation. Especially in active-agent research for medicines and plant protection products, this procedure has already become widely used: so-called high throughput screening (HTS) with up to 100,000 experiments per day is the established state of the art in this context. The development of parallel screening methods has also gained acceptance in other fields, such as catalyst, material and process development. In this case, catalysts, formulations or reaction parameters are varied. The experiments can be planned according to rational, statistical, combinatorial or evolutionary approaches. For the latter applications, the technical requirements when carrying out experiments can be substantially more complex than in the case of HTS for active-agent research (e.g. owing to fluctuating process parameters: temperature, pressure, stirring etc.). For this reason, various parallel systems have to date been described in the literature and introduced to the market.
The most common and simplest systems for carrying out non-pressurized parallel reactions involve reaction blocks, in which solid blocks are drilled with holes to hold a wide variety of sizes of test tubes. The temperature of the test tubes is adjusted via the surrounding block material, either electronically or through the use of a heat exchange fluid. Individual recording of the temperatures in the test tubes is not provided for in the majority of cases, however. The substances contained in the test tubes may be mixed by stirring with an individually adjustable or globally constant stirrer speed. The substances may be added batch-wise via septa. In the majority of cases, it is possible to pass an inert gas over the test tube contents by using a central gas distributor. The blocks are constructed in such a way that it is possible to produce widely differing temperature zones in them at different levels in the form of thick plates (e.g. for reactions under reflux). Such systems are available, for example, from the company H&P, Oberschleiβheim/De under the product name Variomag®. In other known devices for parallel synthesis, the blending in each test tube is carried out using axially guided magnets. The amplitude and frequency of the temperature excursions can be specified. The temperature is adjusted using a hotplate or by immersing the entire reactor block in a cooling mixture. The described reactor blocks can be operated under standard pressure at temperatures between about −80 and about 300° C. The degree of parallel operation, i.e. the number of experiment vessels present in a device, is generally between 10 and 50. The reaction blocks are usually designed in such a way that they can be filled by using an automated pipette (referred to as a liquid handler).
The fact that only a few of the working steps of a synthesis can be carried out with the above-described reaction blocks has resulted in the development of a further generation of reaction blocks. With this new generation, the conditions for the individual test tubes—or, more generally, also referred to as inliners—can be specified and monitored more or less individually and automatically. The dosing of gases and liquids and the isolation and withdrawal of samples are also possible with these reaction blocks. Some of the synthesis parameters can be specified via programmable controllers. Examples of this development are the device known from WO 98/39099 or the reaction block described in U.S. Pat. No. 5,762,881. These systems have been automated in a further step and combined with a liquid dispensing system (liquid handler), so that the method steps from addition of the substances up until injection into an analyzer take place in an automated fashion. The pressure and temperature ranges that can be achieved, however, correspond to those of the simple known reaction blocks described above.
The systems described so far are essentially used for parallel synthesis of organic, chemical substances or synthesis optimization. There has recently been greater interest in equipment which can be used to test material properties even under extreme conditions with parallel methods. Examples of this include superconductors, materials with luminescent properties or catalysts (cf. e.g. WO 96/11878). The specification WO 00/09255 describes a parallel reactor and its use for the production, testing and characterization of materials. The conditions of the process are recorded and monitored. This document describes various options for a parallel reactor: temperature control and monitoring for use in calorimetry, stirring systems for use in viscosity tracking, mechanical oscillators for use in viscosity measurement, pressure sensors for use in determining gas consumption, automated pressure dosing systems, and analysis of experimental data. The commercially available, individually stirrable and globally temperature-adjusted 10 ml individual reactors can be operated at pressures up to about 100 bar. The gas can be supplied with pressure monitoring for each individual reactor.
The respective field of use of the parallel reactor systems referred to in the above-described prior art is restricted in terms of experimental conditions. The absolute upper pressure limit is about 200 bar. Temperatures above 350° C. cannot yet be achieved for individual vessels operated in parallel. Neither is it known whether continuous dosing of gases and/or liquids under these extreme conditions is possible.
It is therefore an object of the present invention to produce an automated parallel reaction system in miniaturized form, which is suitable for even extreme experimental conditions, which is also very easy to adapt to very widespread experimental conditions and, at the same time, can be operated reliably. The term “reactor system” is to be understood below as being a device that consists of a plurality of individual reactors, in which generally chemical or physical methods can be carried out.
The intention with this reactor system is to find test conditions or compositions which can be reproduced optimally under technically realistic operating conditions, by varying the quantity and ratio of the relevant substances and process parameters. The process optimization requires, for example, with already optimized constant reaction partners, that the reaction rate be optimized by further variation of temperature and/or pressure and/or stirring energy. This demands a high level of control and regulation from the technique, since each individual reactor must be controllable and operable separately.
Both points are of high economic importance, so that laboratory discoveries can be implemented more directly into working practice.
Compared with the known reactor blocks, the device is intended to be adaptable in a straightforward way and rapidly to new test conditions. This involves both fast accessibility of the reaction chambers after the end of the test and fast, in particular pressure-tight, resealing of the chambers.
The intention with this device is also for the equipment facilities of a physics/chemistry laboratory to be improved substantially, for example so that varying tasks can be carried out easily with high accuracy and reproducibility in terms of pressure, temperature, stirring rate and test strategy. “Varying tasks” means that temperatures from −80° C. to 400° C. can be set, with an absolute pressure of up to 400 bar. These temperature and pressure ranges place great demands on the technique of the overall system, so that known reactor systems and system components, such as manual valves, controllable fitments, pipeline screw connections, reactors and temperature adjustment systems cannot generally be used.
The extended task comprises carrying out a complete experiment, i.e. the parallel reactor system is to be loaded manually or automatically with the starting components of a test in the required quantity, so that all the subsequent steps of a test can then be carried out automatically under defined conditions. The individual procedures of a test consist in the parallel or sequential combination and/or dosing of one or more liquids and/or gases and/or solids under monitored and defined test conditions. This also involves e.g. being able to carry out a reaction with a short time profile at elevated temperature, while avoiding the long heating time inherent in the design of known reactor systems.
Furthermore, experimental procedures often need to be pressure-controlled and pressure-monitored, e.g. so that a reaction procedure can be controlled and detected from processing standpoints. A further automated facility for controlling an experiment is to be provided by a sampling system in conjunction with suitable analyzers. The discharge and/or controlled extraction of e.g. gaseous minor reaction constituents from the reaction space of individual containers, while retaining the starting components that are used, e.g. by condensation, should in principle be possible.
In the case of carrying out a chemical reaction, the device should be compatible with setting both a reaction condition and a reaction procedure which correspond to those of the technical process. In this context, “experiment” means not just chemical reactions, but also physical state changes of substances being studied: e.g. crystallization, solubility tests, stability tests etc. The device should, in particular, also provide the opportunity to perform multistage chemical synthesis in an automated and continuous way, so that a high rationalization effect can be achieved for laboratories.
Many chemical reactions release large amounts of reaction heat, so that carrying out a test reproducibly with constant parameters requires a powerful, fast-reacting temperature adjustment system. If the reaction scheme is exothermic, then different amounts of reaction heat will be released depending on the test procedure and the test time. The reaction heat released at the start of a reaction is often very high, so that the exothermicity decreases as the test time increases. This fact results in the special requirement for a fast-reacting and powerful, controllable temperature adjustment system. Many reactions take place very rapidly. In this case, it is particularly important for the equipment component masses to be temperature-adjusted, which act as energy stores, to be configured in such a way that a temperature adjustment system reacts quickly, i.e. in the range of only a few seconds, so that the temperature of the reaction in the reaction equipment is kept constant. For this special task, it is often necessary to use different heat exchange media, so that the internal temperature of the reactor can be controlled and kept constant. Air, cooling water or cooled sols may be used as heat exchange media. These coolants act with different intensities owing to their specific heat capacities, so that different quantities of reaction heat may be dissipated by the specific coolant depending on the progress of the reaction. This fast-reacting temperature control of the reaction space also requires additionally controllable valves with particularly short switching times.
When carrying out parallel high-pressure tests (pressure up to 400 bar at temperatures up to 300° C.) on a miniaturized scale (<10 ml working volume), great importance is attached to the sealing of the overall equipment. Even very minor leaks in the overall equipment, e.g. in valves or commercially available cutting-ring or clamping-ring screw connections, render all the results unusable. Consideration of a technical reactor system, with which an integrated test run is to be carried out in parallel from chemical and process standpoints, often shows more than 30 connection points per individual reactor system in the technical layout, at which leaks may occur. If these connection points are multiplied by the degree of parallel operation, there are easily several hundred potential leak points in a very small space, which need to be checked for leaks and make it impossible for the operator to work efficiently with the miniaturized parallel reactor system. For this reason, it is necessary to seek alternatives to the known connection systems, which exhibit a better sealing behavior or avoid such releasable connection points.